Molecular Basis of Anthracycline-Induced Cardiotoxicity and Its Prevention

Horenstein, Mariano; Heide, Richard S. Vander; L’Ecuyer, Thomas

doi:10.1006/mgme.2000.3043

Cited by 202 publications

(137 citation statements)

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“…Doxorubicin (DOX)-induced ROS have been shown as the primary cause of the heart damaging effect of the drug (Horenstein et al, 2000;Xu et al, 2001). In addition, several studies suggested that DOX-induced apoptosis in endothelial cells and cardiomyocytes contributes to the development of DOX-related cardiotoxicity (Childs et al, 2002;Wu et al, 2002;Kluza et al, 2004;Spallarossa et al, 2004).…”

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confidence: 99%

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

et al. 2007

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Doxorubicin (DOX) is an antitumour agent for different types of cancer, but the dose-related cardiotoxicity limits its clinical use. To prevent this side effect we have developed the flavonoid monohydroxyethylrutoside (monoHER), a promising protective agent, which did not interfere with the antitumour activity of DOX. To obtain more insight in the mechanism underlying the selective protective effects of monoHER, we investigated whether monoHER (1 mM) affects DOX-induced apoptosis in neonatal rat cardiac myocytes (NeRCaMs), human endothelial cells (HUVECs) and the ovarian cancer cell lines A2780 and OVCAR-3. DOX-induced cell death was effectively reduced by monoHER in heart, endothelial and A2780 cells. OVCAR-3 cells were highly resistant to DOXinduced apoptosis. Experiments with the caspase-inhibitor zVAD-fmk showed that DOX-induced apoptosis was caspase-dependent in HUVECs and A2780 cells, whereas caspase-independent mechanisms seem to be important in NeRCaMs. MonoHER suppressed DOX-dependent activation of the mitochondrial apoptotic pathway in normal and A2780 cells as illustrated by p53 accumulation and activation of caspase-9 and -3 cleavage. Thus, monoHER acts by suppressing the activation of molecular mechanisms that mediate either caspase-dependent or -independent cell death. In light of the current work and our previous studies, the use of clinically achievable concentrations of monoHER has no influence on the antitumour activity of DOX whereas higher concentrations as used in the present study could influence the antitumour activity of DOX.

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Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

et al. 2007

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“…Although the exact mechanism of cardiotoxicity is not known, the key step in its pathogenesis appears to be the generation of reactive oxygen species, which leads to increased apoptosis, disruption of mitochondrial structure and function, and energy depletion. [2][3][4][5][6] Recent studies have demonstrated a critical role of topoisomerase 2b in anthracycline-induced DNA double strand breaks, which lead to mitochondrial dysfunction and formation of reactive oxygen species. 7,8 In addition, anthracyclines can disrupt intracellular calcium processing, 9 impair pro-survival signaling pathways, 10 and damage cardiac progenitor cells.…”

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confidence: 99%

Anthracycline-induced cardiomyopathy: The search continues

Kim

Bergmann

2017

Journal of Nuclear Cardiology

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“…13,14 Anthracycline cardiotoxicity is thought to be related to direct myocardial injury due to formation of free radicals. 15 Well-recognized clinical risk factors for A-CHF include female sex, younger age at exposure, and radiation therapy involving the heart. 11,16,17 However, these clinical risk factors do not fully explain the wide inter-individual variability in susceptibility to A-CHF.…”

Section: 12mentioning

confidence: 99%

Chronic Health Conditions in Childhood Cancer Survivors: Is it All Treatment-Related—or Do Genetics Play a Role?

Armenian

Bhatia

2009

J GEN INTERN MED

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BACKGROUND: High-intensity, risk-based therapeutic strategies for childhood cancer have resulted in long-term survival rates that now approach 80%. However, the growing population of survivors is at a substantial risk for treatment-related complications that can significantly impact quantity and quality of survival. It is increasingly recognized that many of these complications result from complex interactions between therapeutic exposures and genetic susceptibility.OBJECTIVE: This review is designed to increase general clinician awareness of the ongoing efforts by investigators to understand the interactions between therapeutic exposures and genetic susceptibility to therapy-related complications.RESULTS: Most studies have relied on a biologically plausible candidate gene approach to evaluate genetic susceptibility. This has resulted in the identification of unique genetic polymorphisms that could alter metabolic pathways of therapeutic agents associated with specific adverse events. We highlight some of these findings and discuss their implications for future prevention strategies, as well as their role in elucidating the pathophysiology of these complex diseases. CONCLUSION:Research exploring the role of genetic susceptibility in the development of therapy-related adverse outcomes is still in its infancy. There is a need for continued efforts to study these outcomes in the context of complex gene-gene and gene-environment interactions unique to cancer survivors. A better understanding of the pathogenesis of these outcomes will help develop effective targeted prevention strategies.

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Molecular Basis of Anthracycline-Induced Cardiotoxicity and Its Prevention

Cited by 202 publications

References 42 publications

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

Anthracycline-induced cardiomyopathy: The search continues

Chronic Health Conditions in Childhood Cancer Survivors: Is it All Treatment-Related—or Do Genetics Play a Role?

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